The Poly(ADP ribose)polymerase PARP1 (and PARP2) is an enzyme that binds DNA damage and promotes DNA repair by forming polymers of ADP-ribose which attract repair enzymes. PARP is the key enzyme of single-strand breaks by Base Excision Repair pathway. If left unrepaired, the single-strand breaks convert to double strand breaks during replication that are essentially repaired by Homologous recombination. Therefore, inhibiting PARP is lethal in cells deficient to Homologous Recombination. This observation led to the development of PARP inhibitors to treat cancers that have already mutations disabling their Homologous Recombination capacity.
Two main enzymes are targeted by the PARP inhibitors: PARP1 and PARP2. Under normal conditions, PARP1 and PARP2 are released from DNA once the repair process is underway. However, when they are bound to some PARP inhibitors, PARP1 and PARP2 become trapped on DNA. The trapped PARP-DNA complexes are more toxic to cells than the unrepaired single-strand DNA breaks. There are two classes of PARP inhibitors: (i) catalytic inhibitors that act mainly to inhibit PARP enzyme activity and do not trap PARP proteins on DNA, and (ii) bound inhibitors that block PARP enzyme activity and prevent its release from the Damage site. Though many PARP inhibitors have been developed, their classification in type (i) or (ii) is not clear. It has been proposed that Veliparib could be type (i) and Olaparib, Niraparib, BM673 could belong to type (ii). Moreover, as PARP is involved in many cellular processes, the mechanism of action of PARP inhibitors in tumor cells remains not completely elucidated. Patients are currently considered for PARP inhibitor trials only if they have a particular tumor type (e.g., high-grade serous ovarian cancer or triple negative brain cancer) or their cancer could belong to a relevant molecular subtype (e.g., BRCA½-mutated breast, ovarian, pancreatic, or prostate cancer). Though PARP inhibitor (PARPi) monotherapy showed promising efficacy and safety profiles in the clinic, their major limitations are the necessity of HR deficiency and the rapid emergence of resistance. Many tumors that initially responded to PARPi treatments finally relapsed through compensatory mutations restoring the HR activity or stimulating the activity of alternative repair pathways. Accordingly, the use of PARP inhibitors is limited to particular tumor types and can't be used for treating any cancer.